Project Summary/ Abstract- Project 3 Obstructive sleep apnea (OSA) is a highly prevalent breathing disorder characterized by recurrent episodes of partial and complete airway obstructions that occur exclusively during sleep. OSA poses a significant public health burden due to its being associated with the development of adverse cardiovascular, cognitive, and endocrine conditions. With high relevance to the current proposal, reestablishment of airway patency following an obstructive event is often associated with arousal from sleep (defined by activation of the EEG), resulting in sleep fragmentation, reduced sleep time, and excessive daytime sleepiness in many cases. This disruption of sleep continuity is thought to underlie many of the pathological consequences of OSA. Numerous failed attempts to treat OSA pharmacologically by enhancing ventilatory drive have been limited by unwanted increases in arousability that accompany ventilatory augmentation. Hence, development of methods to enhance ventilatory responses without driving cortical arousal in response to hypercapnia would be a major advance with translational impact for OSA. The detailed circuits underling respiratory versus cortical arousals in response to hypercapnia ? including key cell groups, their targets and their transmitters ? remains, however, incompletely understood. This knowledge gap has hampered the development of pharmacological strategies to treat OSA. The objective in this particular application is to demonstrate a role for CO2-responsive, glutamatergic FoxP2 neurons of the lateral crescent parabrachial nucleus (PBclFoxP2) in driving ventilation independent of arousal. The central hypothesis is that activation of select forebrain inputs to the PBclFoxP2 neurons will enhance the ventilatory response to hypercapnia without driving cortical arousals. The rationale for the proposed research is that successful demarcation of cortical versus respiratory arousal components of hypercapnia circuitry would enable pharmacological treatment strategies for OSA that derive their clinical benefit from the dissociation of the respiratory and arousal responses to hypercapnia. Guided by strong preliminary data, our hypotheses will be tested by pursuing four specific aims: 1) Identify and map presynaptic forebrain inputs to PBclFoxP2 neurons; 2) through transcriptome analysis, uncover unique and ?druggable? receptors on CO2-responsive vlPB cells, including the PBclFoxP2 cell population; 3) define the state-dependent activity of presynaptic forebrain inputs to PBcl neurons; and 4) determine whether signaling from delimited, neurochemically-defined forebrain inputs can augment the ventilatory response to hypercarbia. The approach is intellectually and technically innovative because of its emphasis on forebrain inputs to PBclFoxP2 neurons in the context of ventilatory control, and because it employs a novel combination of newly developed and validated technical approaches. This work is significant because it is one of several key steps in a continuum of research that is expected to lead to the identification and development of a clinically practical drug that can reestablish airway patency in OSA patients without producing sleep disruption.